Proton-triggered nano-drug system with hydrophilic-hydrophobic-dimensional double conversion characteristics and preparation method and application thereof

Abstract

The invention discloses a proton-triggered nano-drug system with hydrophilic-hydrophobic-dimensional double conversion characteristics and a preparation method and application thereof. The system is formed by self-assembly of an aromatic small molecular anti-tumor active drug containing benzene rings, a polyphenol compound and indolecyanine derivatives or CY-series fluorescent dyes. The system isassembled on the basis of an electrostatic acting force and interaction among aromatic rings, has stable hydrophilicity in a neutral environment such as blood and is triggered by protons to be converted into large hydrophobic particles in an acidic environment of tumors in order to push the nano-drug to enter tumor cells and cause endosomal escape; when the neutral environment of the cytoplasm recovers, the system is converted into hydrophilic nano-particles again to release the drug. Meanwhile, the formed proton-triggered nano-drug system with the hydrophilic-hydrophobic-dimensional double conversion characteristics realizes application in the aspects of tumor bioimaging and chemotherapy, photo-thermal and photodynamic combined therapy and the like.

Description

technical field [0001] The invention relates to a nano-medicine system and its preparation method and application, in particular to a proton-triggered nano-medicine system with hydrophilic-hydrophobic-size double conversion characteristics and its preparation method and application. Background technique [0002] Tumor is currently one of the most common causes of death in the world. Usually, free chemotherapy drugs cannot be effectively delivered to the tumor growth site, and it is easy to lead to negative therapeutic effects such as multidrug resistance and severe side effects. Therefore, the preparation of nano-drug carriers for targeted delivery of chemotherapy drugs has received extensive attention. Nano-anti-tumor drugs based on the high permeability and retention effect (Enhanced permeability and retention effect, EPR effect) of solid tumors can target retention and accumulation at tumor sites to improve The therapeutic efficiency of anticancer drugs shows its great po...

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Problems solved by technology

[0003] At present, most of the tumor environment-responsive nano-conversion drug delivery systems rely on the breaking of sensitive chemical bonds, which often require a long chemical reaction time and low conversion efficiency, which will eventually affect the tumor-suppressive therapeutic effect of tumor-targeted nano-drugs.

[0004] Aromatic small molecule anti-tumor active drugs containing benzene rings have good stability due to the benzene ring structure, and have a broad anti-tumor spectrum, strong anti-tumor effect, and definite curative effect. They can act on different links of tumor cell growth and reproduction, inhibit or kill tumor cells. dead tumor cells, but a single use of aromatic small molecule anti-tumor drugs containing benzene rings often produces severe toxic side effects and drug resistance

Polyphenolic compounds are a class of plant secondary metabolites with multiple phenolic groups and stable structure, which can prevent cancer cell proliferation and induce cancer cell apoptosis by capturing or scavenging free radicals (Yang, G. Inhibition of growth and induction of apoptosis in human cancer cell lines by tea polyphenols [J]. Carcinogenesis, 1998, 19 (4): 611-616.), but its free radical scavenging activity is easily affected by many factors

Indocyanine derivatives or CY series fluorescent dyes are fluorescent dyes (Borg R E, Jonathan R. (MPACs): Design Principles&Applications[J].Photochemistry and Photobiology, 2018.), sulfonated CY series fluorescent dyes have good solubility and good dispersibility in aqueous environment, and can localize tumor cells, cells Endocytosis and metabolic distribution in vivo provide real-time imaging detection. Indocyanine derivatives or CY series fluorescent dyes not only have fluorescence and tumor imaging properties based on nuclear imaging, but also can be used as drug carriers to safely deliver chemotherapy drugs to tumors. Indocyanine derivatives are prominently shown to be effective drugs for photothermal and photodynamic therapy, have significant tumoricidal activity through light-dependent cytotoxic activity and reverse chemotherapeutic drug resistance (Shi C, Wu J B, Pan D. Review on near-infrared heptamethine cyanine dyes as theranostic agents for tumor imaging, targeting, and photodynamic therapy [J]. Journal of Biomedical Optics, 2016, 21(5): 50901.), but single indocyanine compounds such as indocyanine Docyanine green, IR820, etc. lack tumor targeting, and have limited uptake rate and affinity for tumors

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